September 2017⎪Vol. 27⎪No. 9

J. Microbiol. Biotechnol. (2017), 27(9), 1549–1558https://doi.org/10.4014/jmb.1705.05032 Research Article jmbReview

Host-Directed Therapeutics as a Novel Approach for TuberculosisTreatmentYe-Ram Kim1,2 and Chul-Su Yang1,2*

1Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea2Department of Bionano Technology, Hanyang University, Seoul 04673, Republic of Korea

Introduction

Tuberculosis (TB), which is caused by infection with

Mycobacterium tuberculosis (MTB), is a global health

problem with significant lethality [1]. In 2015, 10.4 million

people were infected with TB, and 1.8 million people died

because of the disease, including 0.4 million people who

were coinfected with human immunodeficiency virus (HIV).

This is significant because in that same year, 35% of HIV-

related deaths were caused by TB. In 2015, approximately

480,000 people had multidrug-resistant TB (MDR-TB), and

9% of TB patients were infected with an MTB strain that

was classified as extensively drug-resistant TB (XDR-TB).

Treatment of these resistant strains requires a considerably

long duration, with toxic side effects and at a great expense

[2]. For the past 40 years, TB therapy has used a combination

of effective anti-TB drugs to manage active infections.

Generally, TB needs to be treated for 6 months and XDR-TB

for 12–18 months. Furthermore, the current therapy for

XDR-TB is effective in only 50% of cases and imposes a

severe financial burden on patients [3]. Current anti-TB

drugs have other limitations such as adverse effects and

interactions with other drugs [4]. In addition, patients

experience abnormal host inflammatory responses caused

by permanent lung tissue damage [5]. Therefore, novel

therapeutic strategies are required to treat these difficult TB

cases. One novel approach, termed host-directed therapeutics

(HDTs), involves directly targeting host factors rather than

pathogen components [6]. HDTs also reduce pathogen

proliferation and the hyperinflammatory response by

modulating the host immune system [7]. HDTs have

improved clinical outcomes with reduced morbidity,

mortality, organ damage, and TB therapy duration.

Current Anti-TB Drugs

Treatment with first-line anti-TB drugs (Table 1) is a two-

step process that was developed from 1950 to 1960;

treatment lasts for at least 6 months [8]. The first step is an

intensive treatment over 2 months with four first-line

drugs: isoniazid (4-pyridinecarboxylic acid hydrazide, INH),

rifampicin, pyrazinamide, and ethambutol. The second step

is 4 months long and involves continuous isoniazid and

rifampicin administration (short-course chemotherapy) [9].

Received: May 11, 2017

Revised: June 20, 2017

Accepted: June 26, 2017

First published online

July 7, 2017

*Corresponding author

Phone: +82-31-400-5519;

Fax: +82-31-436-8153;

E-mail: chulsuyang@hanyang.ac.kr

pISSN 1017-7825, eISSN 1738-8872

Copyright© 2017 by

The Korean Society for Microbiology

and Biotechnology

Despite significant efforts to improve the treatment of tuberculosis (TB), it remains a prevalent

infectious disease worldwide owing to the limitations of current TB therapeutic regimens.

Recent work on novel TB treatment strategies has suggested that directly targeting host factors

may be beneficial for TB treatment. Such strategies, termed host-directed therapeutics (HDTs),

focus on host-pathogen interactions. HDTs may be more effective than the currently approved

TB drugs, which are limited by the long durations of treatment needed and the emergence of

drug-resistant strains. Targets of HDTs include host factors such as cytokines, immune

checkpoints, immune cell functions, and essential enzyme activities. This review article

discusses examples of potentially promising HDTs and introduces novel approaches for their

development.

Keywords: Tuberculosis, Mycobacterium tuberculosis, multidrug resistance, host-directed

therapeutics, immunomodulatory regulator

1550 Kim and Yang

J. Microbiol. Biotechnol.

Table 1. Current drugs for treatment of tuberculosis (TB).

Classification Drug name Year of discovery Group Structure

First-line

anti-TB drugs

Isoniazid 1952 Group1 : Oral

Rifampicin 1963

Pyrazinamide 1954

Ethambutol 1961

Second-line

anti-TB drugs

Streptomycin 1944 Group 2 :

Injectable aminoglycosides

Kanamycin 1957

Amikacin 1972

Capreomycin 1963 Group 2 :

Injectable polypeptides

Viomycin 1951

Ciprofloxacin 1961 Group 3 :

Oral and injectable fluoroquinolones

Novel Alternative TB Treatments 1551

September 2017⎪Vol. 27⎪No. 9

INH targets an enoyl-(acyl-carrier-protein) reductase and

inhibits mycolic acid synthesis; it is a prodrug that requires

activation by the catalase-peroxidase enzyme KatG [10].

Pyrazinamide inhibits translation by inhibiting the 30S

ribosomal S1 component [11]. First-line drugs such as INH

and pyrazinamide contribute to host defenses against MTB

by triggering the formation of cellular and mitochondrial

reactive oxygen species (ROS) and activating autophagy,

which reduces the MTB-induced proinflammatory response

in macrophages [12, 13]. Ethambutol targets arabinosyl

transferase, which blocks arabinogalactan biosynthesis

[14]. Although these first-line drugs initially show anti-TB

Table 1. Continued.

Classification Drug name Year of discovery Group Structure

Second-line

anti-TB drugs

Levofloxacin 1987 Group 3 :

Oral and injectable fluoroquinolones

Moxifloxacin 1988

Ofloxacin 1980

Gatifloxacin 1992

Para-aminosalicylic acid 1948 Group 4 : Oral

Cycloserine 1954

Terizidone 1965

Ethionamide 1961

Prothionamide 1956

Thioacetazone 1951

Linezolid 1996

Anti-TB drugs are categorized by evidence of efficacy, potency, and case of use.

1552 Kim and Yang

J. Microbiol. Biotechnol.

effects, they have several limitations. These TB treatment

regimens are lengthy, involve drug intolerance and toxicity,

and require the consideration of pharmacokinetic drug-drug

interactions, particularly with anti-HIV drugs for patients

with HIV coinfection [4]. The development of an improved

TB therapeutic approach that is shorter, more effective

against resistant strains, and has fewer drug interactions is

needed [15]. Drug resistance to MTB is typically caused by

inappropriate treatment of active TB infections [16].

MDR-TB is characterized by resistance to isoniazid and

rifampicin. XDR-TB is defined as TB that is resistant to both

isoniazid and rifampicin, as well as to any fluoroquinolone

and at least one of the second-line injectable drugs

(capreomycin, kanamycin, and amikacin) [17]. A World Health

Organization TB treatment report has recommended treating

MDR/XDR-TB using a combination of four or more anti-

TB drugs that are effective against MTB [18].

Second-line anti-TB drugs are used to treat MTB infections

that are resistant to first-line drugs (Table 1: Groups 2, 3, and

4). Group 2 contains injectable anti-TB drugs. Streptomycin

is an aminoglycoside antibiotic, derived from the soil

microorganism Streptomyces griseus, which is used to treat

many bacterial infectious diseases, including TB [2]. This

drug was the first antibiotic used against TB. Streptomycin

interacts directly with the 12S and 16S rRNA components

of the 30S ribosomal subunit, thus inhibiting protein

synthesis [19]. Unfortunately, the use of this antibiotic led

to the rapid emergence of a resistant strain [20]. Because

many MDR-TB patients have resistance to streptomycin, it

is not commonly used for treating MDR-TB [21]. Second-line

anti-TB drugs such as kanamycin, amikacin, capreomycin,

and viomycin target protein synthesis. Kanamycin and

amikacin are aminoglycosides and target the 30S ribosomal

subunit [22]. Capreomycin and viomycin are cyclic peptide

antibiotics with similar structures that bind at the same site

on the ribosome. They target the interface between the 30S

and 50S ribosomal subunits. However, Group 2 drugs

also cause several adverse effects such as ototoxicity,

neurotoxicity, nephrotoxicity, and hypersensitivity. In

particular, aminoglycosides may act as neuromuscular

blocking agents, leading to respiratory failure [23]. Group 3,

composed of fluoroquinolones, inhibits topoisomerase II

(DNA gyrase), topoisomerase IV, and MTB topoisomerase II

[24]. The side effects of fluoroquinolones occur mainly in

the gastrointestinal tract, and 3–17% of patients treated with

fluoroquinolones experience these side effects [23]. Group 4,

oral bacteriostatic second-line anti-TB drugs, includes para-

amino salicylic acid (PAS), cycloserine, ethionamide, and

linezolid. PAS targets dihydropteroate synthase, causing it

to inhibit folate biosynthesis and iron uptake [25]. Common

adverse effects of PAS include nausea, pain, and diarrhea.

PAS can also cause liver inflammation and other allergic

reactions [26]. Cycloserine, a D-alanine analog, inhibits

peptidoglycan synthesis [27] and can have neurological

and psychiatric side effects. [23] Ethionamide is a potent

drug used to treat MDR-TB, and its structure is similar to

that of isoniazid. It is also a prodrug that requires activation

by a monooxygenase encoded by the ethA gene [28]. Similar

to isoniazid, ethionamide targets an enoyl-(acyl-carrier-

protein) reductase and inhibits mycolic acid biosynthesis

[29]. It can also lead to adverse effects in the gastrointestinal

tract, along with hepatotoxicity, neurotoxicity, cardiovascular

effects, and endocrine effects [23]. Linezolid (Zyon) is a

representative drug for eradicating resistant strains. Linezolid

was approved for use against drug-resistant, gram-positive

bacteria in the 2000s [30]. It is a member of the oxazolidinone

antibiotic class, and inhibits protein synthesis by interfering

with the functioning of the 23S rRNA. In addition, linezolid

has in vitro antibacterial activity against MTB, including

against MDR and XDR strains [31]. Moreover, linezolid

had an effect on XDR strains in a study on pulmonary-TB

patients [32] (Table 1). Linezolid therapy can last for less

than 28 days and has mild side effects. This drug affects the

nervous, gastrointestinal, hematologic, hepatic, and metabolic

systems [33]. Second-line anti-TB drugs, which are used to

treat infections resulting from a first-line drug-resistant

strain, have also led to the development of resistant MTB

strains. A spontaneous mutation in a MTB gene targeted by

a current TB drug can result in drug resistance.

The Need for Novel TB Drugs

New drugs for treating MDR-/XDR-TB would ideally

have a novel mechanism of action to circumvent the

current drug resistance. Lower toxicity drugs could reduce

side effects during TB treatment. The period of treatment,

which imposes a considerable economic burden and is

associated with the risk of the development of antibiotic-

resistant strains, also needs to be shortened. To shorten the

treatment period, novel drugs should have potent bactericidal

activity against most types of MTB. Novel drugs should be

effective and safe, and a low dosage frequency would also

be promising. Therefore, the development of dose formulations

and delivery technologies is another requirement for more

advanced TB treatment. Effective drug combination regimens

can also reduce the number of pills required [17].

Novel Alternative TB Treatments 1553

September 2017⎪Vol. 27⎪No. 9

Host-Directed Therapies

HDTs for managing TB are composed of two main

strategies: enhancing the antimicrobial activity to clear

pathogens, and controlling excess inflammation to prevent

permanent lung tissue damage. Current HDTs can potentially

inhibit TB development via diverse host pathways, such as

signal transduction-mediating cytokines, antimicrobial

processes, immune cell regulation, and epigenetic modulation

[34]. The use of HDTs can be expected to reduce the bacterial

burden and fine-tune the host inflammatory response.

HDTs may also require minimal doses and short treatment

durations and may be used in combination with existing

drugs to enhance their overall effect.

Next, this review introduces several representative HDTs

for the treatment of TB (listed in Table 2) [34].

(1) Metformin (Glucophage), which acts as an autophagy

inducer, is currently approved for the treatment of type 2

diabetes. Many studies have shown that the activation of

autophagy leads to the clearance of MTB [35]. Metformin

activates adenosine monophosphate-activated protein kinases,

which are sensors of cellular energy levels [36]. Targeting

adenosine monophosphate-activated protein kinases is

predicted to be a potential anti-TB treatment [37]. Metformin

inhibits MTB growth by inducing mitochondrial ROS

production in vitro. The effect of current anti-TB drugs can

be enhanced by metformin, which was confirmed in both

acute and chronic TB mouse models. Furthermore,

metformin reduced the TB-mediated tissue pathology and

enhanced interferon (IFN)-γ-secreting CD8+ and CD4+

Table 2. Development of host-directed therapeutics for tuberculosis.

Category NameCurrently approved

indication(s)Host target

Developmental

stageRef.

Repurposed

drug

Imatinib Leukemia and gastrointestinal

stromal tumors

Tyrosine kinase Preclinical/clinical

(early phase)

[39]

Verapamil High blood pressure,

chest pain and supraventricular

tachycardia

Voltage-dependent

calcium channels

[34]

Metformin Diabetes AMP-activated protein

kinase activator

[38]

Ibuprofen Pain and fever relief Cyclooxygenase inhibitor [41]

Cytokine

therapy

IL-2 Renal cancer and melanoma Cytokine modulation Clinical

(late phase)

[53]

GM-CSF Acute myelogenous leukemia,

after bone marrow

transplantation

Cytokine modulation [64]

IFN-γ Chronic granulomatous disease Cytokine modulation [65]

Monoclonal

antibody

Adalimumab (Anti-TNFα) Rheumatoid arthritis Cytokine neutralization Preclinical/

clinical

(early phase)

[54]

Tocilizumab (Anti-IL6R) Juvenile arthritis,

Castleman’s disease

Cytokine neutralization [56]

Bevacizumav (Anti-VEGF) Various cancer types Angiogenesis inhibitor [57]

Monoclonal

antibody

Nivolumab

/pembrolizumab (Anti-PD-1)

Melanoma,

various other cancers

Immune checkpoint

inhibitor

Preclinical [45]

Anti-LAG3 Various cancers Immune checkpoint

inhibitor

[66]

Ipilimumab (Anti-CTLA-4) Melanoma,

various other cancers

Immune checkpoint

inhibitor

[67]

Vitamin Vitamin D3 Dietary supplement Innate immune response

activator

Clinical

(late phase)

[44]

Cellular

therapy

Bone marrow-derived

mesenchymal stromal cells

Various inflammatory

indications

Reduction of inflammation

and enhancement of tissue

regeneration

Clinical

(late phase)

[68]

Antigen-specific T cells Cancer and viral infections Targeted killing of

MTB-infected host cells

[68]

1554 Kim and Yang

J. Microbiol. Biotechnol.

T-cell populations. It also reduced the activity of chronic

inflammatory genes in TB patients, in addition to reducing

mortality [38].

(2) Imatinib mesylate (Gleevec) is used to treat leukemia

and gastrointestinal stromal tumors. Imatinib is a small-

molecule kinase inhibitor that blocks tyrosine kinase

enzymes. The therapeutic administration of imatinib

promotes the acidification and maturation of MTB-infected

macrophage phagosomes, reducing the number of colony-

forming units (CFUs) in MTB-infected mice. Furthermore,

imatinib works synergistically with first-line anti-TB drugs to

inhibit drug-resistant mycobacterial strains. At subtherapeutic

concentrations, imatinib strengthens host defenses by

increasing neutrophil and monocyte numbers through

myeloproliferation [39, 40].

(3) Ibuprofen (Advil, Motrin, Nurofen) is a non-steroidal

anti-inflammatory drug normally used as a painkiller and

an antipyretic. This inhibitor of cyclooxygenase inhibits

prostaglandin E2 production and enhances tumor necrosis

factor (TNF) production in macrophages. Although the

direct antimycobacterial activity of ibuprofen is not potent,

it reduces lung tuberculous lesions and bacterial burden

and enhances the survival rate in a mouse model that

mimics active TB [41].

(4) Zileuton (ZYFLO) is a 5-lipooxygenase inhibitor that

inhibits the formation of leukotrienes (LTB4, LTC4, LTD4,

and LTE4) and has been approved to treat asthma. Mice

and humans infected with MTB show decreased IL-1

responses and increased production of type I IFN, resulting

in an eicosanoid imbalance that causes severe TB. Zileuton

reduces weight loss and the number of CFUs and protects

against acute mortality by increasing prostaglandin E2 levels

[42].

(5) Vitamin D3 is a dietary supplement that activates the

innate immune response. Low vitamin D3 levels are involved

in the development of active TB. Vitamin D3 has an

important role in converting 2,5(OH)D into 1,25-(OH)2D3,

which is its active form. This active form induces the

production of cathelicidin, which is an antimicrobial peptide.

After MTB infection, macrophages produce cathelicidin

through Toll-like receptor signaling; thus, vitamin D can

indirectly inhibit MTB [43]. Treatment with both vitamin D3

and 4-phenyl butyrate synergistically enhances cathelicidin

production [44].

(6) Another potent target of HDTs is immune checkpoints.

These immunomodulatory therapeutic strategies have been

studied extensively in cancer research. Programmed cell

death 1 (PD-1) is a protein on the surface of active T cells.

When programmed death-ligand 1 (PD-L1) and PD-L2

associate with PD-1 on the T-cell surface, T cells cannot

attack other cells. Nivolumab and pembrolizumab are PD-1

inhibitors currently used to treat melanomas and other

cancers. Antigen-specific IFN-γ was rescued using a PD-1

inhibitor in TB patients, confirming that nivolumab/

pembrolizumab has potential in treating TB [45]. Cytotoxic

T-lymphocyte-associated protein 4 affects immune checkpoints,

and it is expressed in active TB patients. Antigen-specific

lymphocyte expansion and cytokine expression can be

increased by blocking cytotoxic T-lymphocyte-associated

protein 4 [46].

(7) Cytokine therapy could be an alternative method to

limit the currently used TB chemotherapy. This method

uses immunomodulators to boost the immune system [47].

Cytokines contribute to various cellular responses, including

immune signaling in TB. Cytokine therapy induces a

proinflammatory immune response and antimicrobial

activity, which can be beneficial in treating TB. IFN-γ plays

a major role in the host defenses against MTB. IFN-γ, as a

prototypical product of Th1 cells, promotes the secretion of

Th1 cytokines (such as IL-12) and inhibits Th2 cytokines

(such as IL-4). In addition, IFN-γ upregulates class I and II

antigen-presenting cells and increases the antimicrobial

activity of macrophages. Mutations in the IFN-γ receptor gene

result in high susceptibility to mycobacterial infections

[48]. Granulocyte macrophage colony-stimulating factor

(GM-CSF) increases the number of macrophages, leading to

an enhanced inflammatory response. GM-CSF also shows

antimycobacterial activity in human macrophages [49].

Studies on GM-CSF-deficient mice showed that GM-CSF

plays critical immunomodulatory roles in the host defenses

against pulmonary TB [50]. Moreover, IL-2 induces the

expansion of T cells. However, recent studies have shown

that IL-2 promotes CD4+CD25+ regulatory T-cell expansion,

which suppresses the T-cell response [51]. Some clinical

trials testing the effectiveness of IL-2 against TB have been

reported [52, 53].

Excessive proinflammatory cytokine production causes

permanent host tissue damage. Therefore, regulating

cytokine production could be an alternative approach to

treat TB by reducing destructive inflammation. The current

monoclonal antibody used for cytokine neutralization

modulates inflammatory responses. The anti-TNF therapeutic

agent adalimumab has been previously used to treat TB

[54]. IL-6, which accelerates the severity of disease in TB

patients, is a promising candidate. Blockage of the IL-6/IL-6

receptor pathway is considered therapeutic in treating

various diseases [55]. The use of a monoclonal antibody,

along with the IL-6 receptor blockage, enhances anti-TB

Novel Alternative TB Treatments 1555

September 2017⎪Vol. 27⎪No. 9

T-cell responses, decreases severe pathology, and reduces

the MTB burden in mice [56]. The anti-vascular endothelial

growth factor (anti-VEGF, bevacizumab) monoclonal antibody

inhibits TB by normalizing vasculature, increasing the

delivery of small molecules, and decreasing hypoxia in

tuberculous granulomas [57]. Therefore, the anti-VEGF

monoclonal antibody may increase the efficacy of current

treatment regimens.

Cell-based therapies are considered effective alternative

therapies in treating cancer and infectious diseases. In

addition, such therapies might decrease tissue-destructive

inflammation, enhance organ repair, and intensify antigen-

specific immune responses [58].

Several studies have focused on immunomodulatory

functions that show antimycobacterial activity [59-61].

Previously, we developed a novel treatment strategy for

treating an intracellular parasite infection, which might be

used as an HDT strategy against TB. We investigated

interactions between the intracellular parasite Toxoplasma

gondii and host macrophages and clarified the cellular

signaling involved in this interaction. T. gondii dense

granule antigen (GRA) 7 is essential for the innate immune

response and acts through an association with TNF receptor-

associated factor 6 (TRAF6) via myeloid differentiation

primary response gene 88. The interaction between GRA7

and TRAF6 confers a protective effect against T. gondii

infection in vivo [62]. We performed further experiments to

determine whether GRA7 modulation of the innate

immune response could work for other infectious diseases

such as TB. We found that GRA7 interacted with many host

proteins, including important host immune response

regulators. We showed that the protein kinase C alpha-

mediated phosphorylation of GRA7 is essential for the

interaction between apoptosis-associated speck-like protein

Fig. 1. Comparison between current anti-tuberculosis (TB) drugs and potential host-directed therapeutic (HDT) strategies for

treating TB.

Current anti-TB drugs have been developed by targeting pathogenic factors such as bacterial proliferation. A spontaneous mutation in one of the

genes that is targeted by these antibiotics can lead to the emergence of drug-resistant TB strains. To overcome the limitations of current anti-TB

drugs, the development of new drugs is necessary. HDTs directly affect host factors. Strategies for developing anti-TB HDTs have been verified in

several TB studies. IL-2, Interleukin-2; GM-CSF, Granulocyte macrophage colony-stimulating factor; IFN-γ, Interferon gamma; PD-1, Programmed

cell death protein 1, LAG3, Lymphocyte activation gene 3; CTLA-4, Cytotoxic T-lymphocyte-associated antigen 4; GRA7, Toxoplasma gondii dense

granule antigen 7.

1556 Kim and Yang

J. Microbiol. Biotechnol.

containing a carboxyl-terminal CARD and phospholipase

D1. These interactions induced antibacterial activity against

TB. GRA7 controlled the innate immune response by

interacting with host cell proteins. Our current studies

have established proof of concept for developing novel

HDT strategies that could serve as alternatives to treat TB

[63] (Fig. 1).

In conclusion, by directly targeting host factors, HDTs

enhance immune responses and fine-tune inflammation,

and can thus be used to treat bacterial, viral, and parasitic

infectious diseases. Current treatment for MTB-mediated

TB has several limitations, including the long period of

treatment, emergence of resistant strains, and toxicity of

the drugs. These limitations increase the need for developing

novel TB treatment strategies. The present review focused

on potential novel HDTs that may be used to treat TB.

HDTs play a role in the clearance of MTB and regulation of

excess inflammatory responses to protect the host from

permanent organ damage. Furthermore, the combination

of HDTs with current TB drugs reduces drug dosages and

improves clinical outcomes. HDTs can be used to target

many pathways, and as such can be used to verify the

antimycobacterial activity of an approved drug (re-purposed

drugs), inhibit immune checkpoints, and modulate cytokine

production. We have shown that antigens derived from

the intracellular parasite T. gondii modulate the immune

response and might be promising for treating MBT infection.

However, the potential uses of HDTs need to be explored

further. Because HDTs directly interact with host factors,

various factors need to be considered prior to their

application. Furthermore, it is difficult to establish HDTs

that manipulate a human factor using animal models.

Because HDTs target complex pathways, there should be

detailed investigations into the potential side effects of HDTs.

Understanding the host immune response in TB-mediated

immune pathology is very important in HDT research.

Acknowledgments

This work was supported by a research fund of Hanyang

University (HY-2014-N).

Conflict of Interest

The authors have no financial conflicts of interest to declare.

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